Prominent U-waves without QT prolongation in X-linked creatine transporter deficiency caused by SLC6A8 variants

Abstract: BACKGROUND Creatine transporter deficiency (CTD) is a rare X-linked disease caused by SLC6A8 variants, which impair ATP-dependent energy metabolism in neurons and myocytes. Although the neurologic and muscular manifestations are well characterized, the cardiac phenotype remains poorly understood. Early clinical reports and a transgenic mouse model have raised concerns about possible associations with corrected QT (QTc) interval prolongation and dilated cardiomyopathy.
OBJECTIVE This study aimed to characterize the cardiac phenotype of male patients with CTD.
METHODS This cross-sectional study prospectively included male patients with CTD with confirmed SLC6A8 pathogenic variants. A systematic cardiological evaluation was performed, including 12-lead resting electrocardiogram (ECG), ambulatory ECG (Holter monitoring), transthoracic echocardiography, and biological analysis.
RESULTS 23 male patients with CTD (median [interquartile range] age 17.1 years [13.5–20.5]) with 20 distinct SLC6A8 variants were included. Prominent U-waves were observed in 82.6% of resting ECGs and 95% of ambulatory ECGs, and biphasic Twaves in 30.4% and 90%, respectively. No patient had a prolonged QTc interval (median [interquartile range] QTc interval 431 ms [411–443]) when the U-waves were excluded. Repolarization abnormalities were not secondary to electrolyte disorders.
No sustained arrhythmias or conduction disorders were observed. No patient reported syncope or cardiac arrest. Transthoracic echocardiography revealed no cardiomyopathy or congenital heart defects. 2 patients had mildly elevated N-terminal probrain natriuretic peptide with no clinical or imaging abnormalities.
CONCLUSION This study highlighted an atypical ventricular repolarization pattern in patients with CTD (prominent U-waves and biphasic T-waves) without QTc interval prolongation. Long-term follow-up data are needed to establish its prognosis, but it must be distinguished from long-QT syndrome. No patient met diagnostic criteria for cardiomyopathy or congenital heart defect.

Link to article: https://www.heartrhythmjournal.com/article/S1547-5271(25)03068-1/fulltext

Authors: Antoine Delinière, MD, PhD, Chloé Mulatier, MD, David Cheillan, PharmD, PhD, Farha Gheurbi, MSc, Marion Buchy, MSc, Nathalie Dufay, PhD, Anne Moulin-Zinsch, MD, Claire Bertail-Galoin, MD, Maëva Sabour, MD, Mariama Aarab, MD, Thomas Perouse de Montclos, MD, Diane Ouvrier-Buffet, MD, Aymeric Boisson, MD, Bertrand Stos, MD, Mohamed Rharbaoui, MD, Ganaëlle Remerand, MD, Christine Barnerias, MD, Anaïs Brassier, MD, Alice Goldenberg, MD, Agathe Roubertie, MD, PhD, Laurence Lion-François, MD, Stéphanie Marignier, MD, Pascale De Lonlay, MD, PhD, Fanny Mochel, MD, Vincent Navarro, MD, PhD, James Lespinasse, MD, Didier Lacombe, MD, PhD, Renaud Touraine, MD, Sylvain Rheims, MD, PhD, Vincent des Portes, MD, PhD, Philippe Chevalier, MD, PhD, Aurore Curie, MD, PhD

Key terms: CTD, clinical study, cardiovascular symptoms, male patient, pediatric patient, adult patient